In order to treat effectively and repair the disease of drug addiction, the critical mediators and defects in the brain must be known. While some mediators and defects or changes due to drugs are known, all the critical ones may not be fully known or understood. This proposal deals with a relatively new neurochemical that appears to play a role in the action of psychostimulant drugs such as cocaine and methamphetamine. This neurochemical is actually a small group of peptides referred to as CART peptides. They were discovered by giving animals cocaine or amphetamine, and CART peptides are found in many brain regions involved in reward and reinforcement. Moreover, some CART peptides, upon injection into the brain, produce effects that are psychostimulant-like suggesting that they may mediate, at least partly, some of the actions of these drugs. This proposal further characterizes the behavioral effects of CART peptides and explores the neurochemical and neuroanatomical bases for these effects. All known active CART peptides will be injected into brain regions associated with reward and reinforcement and it will be noted if they produce effects similar to those produced by psychostimulants. The interaction of CART peptides with cocaine and dopamine will be carefully analyzed. The precise location of endogenously occurring CART peptides will be delineated by light and electron microscopy in drug dependence-related neurocircuits. Taken together, these findings will substantially increase our knowledge of the role of CART peptides in the action of psychostimulant drugs, may enhance our understanding of the process of drug dependence, and may suggest targets for development of medications for psychostimulant abusers.